tbuckley/cabot-search huggingface dataset:
The age-adjusted rates and treatment of typical carcinoid tumors of the lung.
Authors: Anisha P Valluri, Rick Voland, John M. Varlotto, Yousef Michael Shweihat, Mark Michael Cooper, Dani Zander
Journal: Journal of Clinical Oncology (2022)

e20507 Background: Pulmonary typical carcinoid tumors(TC) are rare and the treatment of these tumors has not been well studied. The purpose of our investigation is to find whether or not these tumors are increasing in frequency and to assess the value of different treatment options. Methods: The National Cancer Database was queried from the years 2004-2015 for those patients who underwent a surgical resection((bi)lobectomy(L+) or sub-lobar resection(L-)) of TC. Multi-variate analysis for overall survival (OS) in surgical patients was used for propensity matching to determine the benefits of (L-) vs (L+) and to assess the role of chemotherapy or radiation in node positive disease(N+). SEER-18 was used to estimate the age-adjusted rates of TC and the percentage of N+ tumors during the years of our study. Results: With a median follow-up of 62.1 months, 16337 patients underwent surgical resection of TC of which 7846, 7538, 644, 302, and 7 patients had NX, N1, N2, and N3 disease. The rate of TC per 100,000 population progressively and significantly increased from 3.2 to 5.4 while the rate of node positivity remained flat at 0.3-0.4/100,000 population. Adjuvant therapy was given to 155 patients with radiation and 945 with chemotherapy. In the total population, a significant OS benefit was noted in those undergoing a L+ compared to L- (HR = 1.35 p &lt; 0.0001), which was not seen in patients with node negative tumors &lt; 2cm, but was seen in node negative tumors &gt; 2cm (HR = 2.00, p 0.0088) and N1(HR = 3.2, P &lt; 0.0001) and N2 disease(HR = 4.2, p &lt; 0.0001. N2(HR = 2.25, p &lt; .0001 and N1 disease(HR = 1.53 p = 0.0021) had a significant lower OS than N0 disease which were not improved not with radiation therapy(p-value 0.4055) and worsened with both adjuvant chemotherapy(median OS HR p value = &lt; 0.0001). Conclusions: Typical carcinoid tumors are increasing in the US population and should undergo a lobectomy when the size &gt; 2cm or when node positive disease is present. Despite the worse prognosis of patients with node positive disease, radiation did not improve and chemotherapy worsened OS.
Modification of adipose mesenchymal stem cells-derived small extracellular vesicles with fibrin-targeting peptide CREKA for enhanced bone repair
Authors: Qi Wu, Xiaoling Fu, Xian Li, Jing Li, Weiju Han, Yingjun Wang
Journal: Bioactive Materials (2022)

The process of bone repair is highly regulated by a large number of bioactive factors. Thus, a "cocktail" of bioactive factors supplemented to the defect sites is desirable for bone repair. In this regard, small extracellular vesicles (sEVs) derived from mesenchymal stem cells hold great potential in tissue repair. Nevertheless, the poor homing and retention of sEVs greatly limited their possible clinical application. In the present work, DMPE-PEG-CREKA was inserted into the membrane of sEVs released from adipose-derived mesenchymal stem cells to obtain CREKA functionalized sEVs (CREKA-sEVs), which could target fibrin to accumulate and retain in bone defects. Our results showed that CREKA-sEVs, like sEVs, promoted the osteogenic differentiation of BMSCs, the angiogenic property of HUVECs, and modulated the polarization of macrophages in vitro. Furthermore, due to the improved fibrin-binding and retention capacity of CREKA-sEVs, they enhanced the bone repair substantially in the rat femoral defect model. This study provided a new strategy to improve the therapeutic efficiency of sEVs and showed that CREKA-sEVs had great application value in bone tissue repair.
Use of right kidneys versus left kidneys in living-donor robot-assisted kidney transplantation: A comparative analysis
Authors: A. Abella Serra, B. Etcheverry Giadrosich, X. Bonet Puntí, P. Sanz Serra, P. De Pablos Rodriguez, M. Fiol Riera, C. Couceiro Monteagudo, A. Manonelles Montero, J.F. Suárez Novo, L. Riera Canals, F. Vigués Julià
Journal: European Urology (2022)
S100A9 blockade ameliorates cardiac dysfunction and reduces myocardial immune infiltration in experimental autoimmune myocarditis
Authors: G Jakobsson, M Mulholland, A Grentzmann, I Ljungcrantz, S Rattik, D Engelbertsen, A Schiopu
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Swedish Heart and Lung Foundation and Swedish Research Council Background/Introduction Autoimmune myocarditis is characterized by non-ischemic inflammatory heart injury, leading to myocardial damage and impaired cardiac function. S100A9 is an inflammatory alarmin present in large amounts in neutrophils. The role of S100A9 as a potential treatment target in myocarditis has not been fully explored. Aim We sought to investigate the impact of S100A9 blockade in experimental autoimmune myocarditis and assess the effects of treatment on cardiac function and immune infiltration. Methods BALB/C mice were immunized with αMHC peptide emulsified in Complete Freunds Adjuvant at day 0 and day 7 to induce the disease. The water-soluble small-molecule S100A9 blocker ABR-238901 was given continuously in drinking water starting on day 7. Echocardiography was performed weekly from day 21 to day 42 (n=11/group). For flow cytometry analysis, mice were sacrificed at day 21 (n=10/group). Results S100A9 blockade improved left ventricular ejection fraction [52.33% vs 44.87% on day 42 (p&amp;lt;0.001)]. Cardiac output was significantly improved on day 21 (12.69 vs 11.05 mL/min, p&amp;lt;0.05). We found a significant reduction of inflammatory cardiac infiltrates at day 21, characterized by reduced number of macrophages (p&amp;lt;0.05), neutrophils (p&amp;lt;0.01) and CD4+ T cells (p&amp;lt;0.05). The cardiac draining lymph nodes contained fewer dendritic cells (p&amp;lt;0.01), T cells (p&amp;lt;0.05), as well as reduced numbers of inflammatory CD4+ cells producing IL-17 (p&amp;lt;0.05). Conclusion Therapeutic S100A9 blockade inhibits inflammatory cardiac infiltration and improves cardiac function in experimental autoimmune myocarditis. Our findings highlight the important role of S100A9 in the pathogenesis of myocarditis and identify S100A9 blockade as a possible novel therapeutic avenue.
Pan-cancer analysis of BRAF alterations and tumor-specific mechanisms of activation.
Authors: Hannah E. Bergom, Eamon P. Toye, Xiaolei Shi, Charles J. Ryan, Emmanuel S. Antonarakis, Justin Hwang
Journal: Journal of Clinical Oncology (2022)

e17005 Background: BRAF is a proto-oncogene that is altered in various cancers and is a druggable target. Particularly, the selective BRAF kinase inhibitors Dabrafenib and Vemurafenib are FDA approved for melanoma and thyroid cancer that harbor the activating BRAF V600 hotspot mutations. In pre-clinical studies, activated BRAF promotes tumor cell function across many additional cancer types in which therapeutics have not been considered. We propose that identifying BRAF-activated cancers will guide future pre-clinical investigations and potentially expand the usage of existing BRAF-targeting therapeutics. Methods: We utilized bioinformatics to investigate the molecular profiles of pan-cancer cohorts from two platforms based on distinct sequencing technology. This included a custom curated dataset (whole exome, 6 studies, 39 cancer types, n = 12,019) and GENIE9.1 (targeted gene panel, 62 cancer types, n = 78,619). Studies were included based on genomic modalities (copy number alterations, mutations, gene fusions). We cataloged the frequency and all types of BRAF genomic alterations pan-cancer. We also examined other genomic features, including tumor mutational burden (TMB) and fraction of the genome altered (FGA), and their association with types of BRAF alterations across cancer types. Results: In both platforms, we found that BRAF alterations were observed across over 80% of cancer types. Melanoma, thyroid, and colorectal tumors exhibited the greatest rates of mutations. Regarding gene body rearrangements, we noted endocrine-driven cancers including ovarian and metastatic prostate tumors (mPC) exhibited relative robust rates of amplification. In addition, thyroid carcinoma and mPC harbored recurrent BRAF gene fusion events. In mPC, we found that the BRAF gene fusions often included an N-terminus gene fragment from known androgen-target genes (TMPRSS2 and SND1). These fusion events represented a dysregulated hormone-driven mechanism of BRAF activation. We also found that hotspot missense mutations were cancer-type specific, including K601 hotspots in mPC, G469 hotspots in non-small cell lung cancers, and G466 hotspots in ovarian cancers. Lastly, BRAF-amplified endocrine tumors harbored a 1.5-fold increase in FGA medians, whereas BRAF-mutated lung and colorectal tumors exhibited a 1.6-fold increase in TMB medians. Conclusions: Our molecular analysis revealed that cancers accrued activated BRAF through cancer-type-specific and divergent genomic mechanisms. These molecular features provide genomic evidence to expand the application of BRAF-targeted therapies in additional cancer lineages, including mPC. BRAF mutations were also associated with genomic biomarkers, such as TMB, which may predict response to immune therapies. This suggests that BRAF alterations can be considered as an additional feature to aid therapy selection.
<i>MET</i> kinase mutations in lung cancer patients.
Authors: Louise Kalmuk, Clotilde Descarpentries, Celine Mascaux, Camille Munck, Zoulika Kherrouche, Eric Wasielewski, Lucie Ulmer, Olivier Farchi, Fabienne Escande, Michele Beau-Faller, Alexis B Cortot
Journal: Journal of Clinical Oncology (2022)

e21014 Background: Although mutations in the kinase domain of MET are well described in papillary renal cell carcinoma, they are rare and poorly studied in lung cancer, but could constitute a new therapeutic target given the availability of potent MET inhibitors. The characteristics of patients with MET kinase mutation in lung cancer are still unknown. Our objective was to describe the demographic, clinical and biological characteristics of these patients, and analyze their survival. Methods: We conducted a multicenter retrospective study including patients with lung cancer harboring a MET kinase mutation. Patients who had already received treatment with a MET TKI before the MET kinase mutation was found were excluded. Results: We identified 37 patients with a MET kinase mutation. Among them, 2 had already received a MET inhibitor and in 8 cases, the data were not accessible. A total of 27 patients were included in the final analysis, including 17 males (63%) and only 2 (8%) never smokers. The median age was 64 (range 43-86). Most patients had adenocarcinoma (n = 25, 93%). 19 patients were diagnosed at an advanced stage. The main metastatic sites were brain (n = 8, 42%), bones (n = 7, 37%) and lungs (n = 5, 19%). PDL1 expression level was available for 21 patients, and was &lt; 1%, 1-49% and ≥50% in 4 (19%), 5 (24%) and 12 (57%) patients respectively. MET kinase mutations involved exon 15, 16, 17, 18 or 19 in 6 (22%), 7 (26%), 7 (26%), 3 (11%) and 4 (15%) patients respectively. The 2 most common mutations were H1112Y (4 patients) and H1097R (3 patients). 18 patients (67%) had a concurrent alteration by NGS including TP53 mutations (n = 11, 41%), KRAS mutations (n = 6, 22%) and NRAS mutations (n = 3, 11%). Overall, co-alterations involving known driver oncogenes were detected in 13 patients (48%). 19 patients received a first-line systemic treatment for advanced disease. Median progression-free survival with chemotherapy and immunotherapy was 10.5 and 6.4 months, respectively (p = 0.55). Median overall survival was 12.2 months. No patient received a MET inhibitor. Conclusions: MET kinase mutations are not associated with specific clinical characteristics and frequently occur together with other oncogene mutations. These results suggest that these mutations may not be sufficient to drive carcinogenesis by themselves.
The adoption of relugolix for treatment of prostate cancer (PCa) in a large community medical oncology practice.
Authors: Victoria Schuster, Dipen Patel, Martin Christopher Barnes, George Cyriac, Harry Staszewski
Journal: Journal of Clinical Oncology (2022)

e13541 Background: Relugolix was approved by the FDA in late 2020 as an oral gonadotropin-releasing hormone (GnRH) receptor antagonist for the treatment of adults with advanced PCa. The approval was based on a large randomized trial (Shore et al NEJM) of patients with evidence of biochemical or clinical relapse after local primary intervention with curative intent (50%), newly diagnosed mCSPCa (23%), and advanced localized disease not suitable for primary surgical intervention with curative intent (28%). Our study aims to observe the adoption of relugolix in a large community-based medical oncology practice with affiliated urologists. Methods: A retrospective study using our EMR identified 39 males with PCa for whom relugolix was initiated between January 2021 and December 2021. The charts were analyzed for demographics, indications for treatment, barriers encountered to initiation of treatment, duration of therapy, previous therapies, specialty, primary insurance, and cardiovascular history. Results: Thirty-nine (39) patients with either localized PCa (40%) or with metastases to lymph nodes or distant sites (51%) were recommended initiation of relugolix by either urology (26%) or oncology (74%). Of these, 77% actually started the medication. 9 patients did not start therapy, of which 3 were due to insurance denial, 1 due to death, 2 changed their mind, and 3 did not start for unclear reasons. Medicare covered 56% of the patients. Cardiovascular disease was notable in 87%. 28% switched from another ADT due to intolerance, 10% started relugolix due to progressive disease, and 33% started as initial ADT. 13% discontinued within 6 months. Of these, 1 completed planned therapy, 3 were intolerant, 1 was switched to alternate therapy due to progression, and 1 had complications due to COVID. In comparison, 689 patients initiated ADT with leuprolide over the same time. Conclusions: ADT using GnRH agonists or antagonists form the backbone of PCa treatment, typically given as injections. The HERO trial showed that relugolix, a newer oral therapy, is associated with lower rates of cardiovascular events compared to leuprolide. While having at least one cardiovascular risk factor is a consideration for patients to either start with or switch to relugolix, the large majority of our patients still received first-line therapy with leuprolide. This study demonstrates limitations to initiating relugolix including financial constraints (e.g., insurance coverage), patient preference, and medication intolerance.[Table: see text]
ATRT-24. CDK7 Inhibition in AT/RT
Authors: Andrew Morin, Darya Wodetzki, Bethany Veo, Angela Pierce, Shadi Zahedi, Michele Crespo, Sujatha Venkataraman, Rajeev Vibhakar, Jean Mulcahy-Levy
Journal: Neuro-Oncology (2022)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are CNS tumors with a 5-year survival of ~35%. AT/RT is characterized by loss-of-function mutations in the SMARCB1 component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) complex. Based on preliminary CRISPR-Cas9 gene essentiality screen results identifying AT/RT vulnerabilities, we hypothesized that interaction between CDK7 and the SWI/SNF complex via SMARCB1 provides a potential target to improve clinical survival of patients. CDK7 expression was identified by microarray in AT/RT, medulloblastoma, glioblastoma and normal brain. Established cell lines (BT12, BT16, CHLA06), patient derived lines (MAF-737, MAF-1298, MAF-1337), normal human astrocytes (NHA) and NIH3T3 mouse embryonic fibroblast cells were utilized for in vitro response to CDK7 inhibition. Murine cerebellar xenografts of MAF-737 were utilized to evaluate genetic and pharmacologic response to CDK7 inhibition. The NCI Approved Oncology Drugs (AOD-9) Panel was evaluated with an IC25 dose of CDK7 inhibitor THZ2 to identify potential synergistic combinations. CDK7 is up-regulated in AT/RT compared to other brain tumors or normal brain. In vitro, AT/RT cells are highly susceptible to CDK7 pharmacologic inhibition with nM IC50 levels. AT/RT cells with shRNA against CDK7 implanted in vivo show significantly reduced growth. Evaluation of in vivo tumors treated with THZ2 demonstrate decreased Ki-67 and reduced pRBP1 demonstrating effective inhibition of the target as well as a decrease in cell proliferation. Combination therapy of THZ2 with the AOD-9 Panel found significant synergy with antimetabolite therapies, specifically pemetrexed, pralatrexate, and methotrexate. There was no synergy with other standard chemotherapy. Our findings demonstrate that CDK7 is highly expressed in AT/RT and necessary for proliferation of AT/RT cells, suggesting it as a potential therapeutic target. Antimetabolites, which are currently used in several AT/RT protocols, synergized with CDK7 inhibition offers a potential future combination therapy for patients.
Human papillomavirus (HPV) vaccine hesitancy trends in the United States.
Authors: Eric Adjei Boakye, Dina K Abouelella, Mrudula Nair, Nosayaba Osazuwa-Peters
Journal: Journal of Clinical Oncology (2022)

10550 Background: Despite the human papillomavirus (HPV) vaccine being safe and effective at preventing HPV-associated cancers, vaccine update is low. Several factors have been identified as barriers to getting the HPV vaccine. However, it is unclear if these factors have changed since vaccine licensure. Thus, we assessed trends in the top five reasons for vaccine hesitancy in the last decade in the US. Methods: We analyzed the 2010–2019 National Immunization Survey–Teen data, a national survey representative of the US adolescent population. We identified adolescents (n = 16,383) who had received zero dose of the HPV vaccine (unvaccinated adolescents). Parents of unvaccinated adolescents were asked how likely they will vaccinate their child in the next 12 months. Parents who responded with “not too likely”, “not likely at all” or “not sure/don’t know” (vaccine hesitant) were asked what the reasons are for their hesitancy. The top five most cited reasons for vaccine hesitancy: “not necessary”, “safety concerns”, “lack of recommendation”, “lack of knowledge”, and “not sexually active” were included in the study. Joinpoint regression estimated yearly increases/decreases in these reasons using annual percent changes. Results: The proportion of unvaccinated adolescents whose parents cited “safety concerns”’ as a reason for HPV vaccine hesitancy decreased from 2010 to 2012 but increased significantly from 2012 to 2019 at an average of 8.6% annually. The proportion of unvaccinated adolescents whose parents cited “not sexually active” as a reason for HPV vaccine hesitancy decreased on average by 33.1% from 2010-2012 and then at an average of 11.5% in the remaining years. The proportion of unvaccinated adolescents whose parents cited “not necessary” as a reason for HPV vaccine hesitancy decreased from 2010-2012 but significantly decreased by an average of 11.0% yearly from 2012-2019. The proportion of unvaccinated adolescents whose parents cited “lack of recommendation” and “lack of knowledge” as reasons for HPV vaccine hesitancy decreased over the 10-year period though not statistically significant. Conclusions: There was a decrease in most of the reasons cited by parents for vaccine hesitancy except vaccine safety which has been increasing from 2012 to 2019. These findings suggest an urgent need to combat the rising sentiment of safety concerns among parents of unvaccinated children to increase HPV vaccine confidence.
DIPG-59. Blood Brain Barrier (BBB) modulation using Cadherin peptides in the treatment of Diffuse Midline Glioma of the Pons (DMG-P)
Authors: Stacey Line, Babu Velayuthan Sajesh, Kelly Schwinghamer, Vinith Yathindranath, Maria Tsoli, David Ziegler, Teruna Siahaan, Donald Miller, Magimairajan Issai Vanan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Diffuse midline glioma of the Pons (DMG-P) is the most common brainstem tumor of childhood and is universally fatal. The BBB is frequently intact in DIPG and restricts entry of systemically administered conventional and biological therapies. We have synthesized and validated synthetic cadherin peptides (HAV6, HAVN1) that cause transient opening of the BBB by preventing the dimerization of the extracellular membrane bound VE-Cadherin in the vascular endothelium. METHODS: We used DMG-P tumor conditioned media (TCM) and co-cultures in two in-vitro model systems (trans well inserts, Blood Brain Tumor Barrier microfluidics model (BBTB-DMG-P microchip)-using Human Brain microvascular endothelial cells (HBMVECs) / SF8628 (DMG-P PDX) and validated the in-vitro findings in a DMG-P orthotopic murine model using RA055. The permeability of different molecular weight markers [(Gd-DTPA, IRDye 800CW PEG, rhodamine 800 (R800)] were examined in presence / absence of HAV6 / HAVN1 peptides. RESULTS: The BBTB integrity is maintained in-vitro as evidenced by decreased permeability of all the agents across the barriers in the TCM / co-culture models. Addition of HAV6/ HAVN1 peptides in-vitro increased the permeability of all the agents across the barriers. The permeability of R800 increased in the presence of Elacridar (P-gp inhibitor). The BBB was intact in the DMG-P murine model, as evidenced by minimal Gd-DTPA contrast enhancement in T1 weighted MRI images. Administration of HAV6 / HAVN1 peptides resulted in Gd-DTPA contrast enhancement of the tumor at 5- and 10-minutes post injection. CONCLUSION: Our data confirms that the BBTB is intact in DMG-P and can be transiently modulated using synthetic cadherin peptides. Transient BBTB opening using synthetic peptides will help BBB non-penetrant chemotherapy drugs like Vincristine/Mitoxantrone and biological therapies to reach intra-tumoral therapeutic levels and improve therapeutic efficacy.